Microtubule‐Targeting Chemotherapy Causes Mitochondrial Dysfunction in Heart and Skeletal Muscle
Bibliographic record
Abstract
RATIONALE A variety of chemotherapies are associated with muscle dysfunction but the mechanisms are poorly understood. Emerging evidence suggests doxorubicin (DNA targeted chemotherapy) impairs mitochondrial respiration and increases H 2 O 2 emission. However, whether other chemotherapies create similar mitochondrial dysfunctions in muscle is unknown. An emerging model proposes that microtubules can inhibit mitochondrial ADP import/ATP export by blocking outer membrane voltage‐dependent anion channels (VDAC). We hypothesized that microtubule‐targeting chemotherapies (taxol, microtubule stabilizer; vinblastine, microtubule destabilizer) may alter ADP control of oxidative phosphorylation by changing VDAC‐permeability to ADP. We also hypothesized that these chemotherapies would alter mitochondrial H 2 O 2 emission considering ADP suppresses H 2 O 2 emission from mitochondria during oxidative phosphorylation. METHODS Mitochondrial ADP‐stimulated respiration and suppression of H 2 O 2 emission were assessed in permeabilized muscle fibres from skeletal muscle (soleus, extensor digitorum longus; EDL) and heart left ventricle following incubation with taxol and vinblastine for 2 and 1hr respectfully, at 4°C. RESULTS Diverse responses were observed with both microtubule stabilizing (taxol) and destabilizing (vinblastine) drugs. However, a consistent pattern emerged in heart whereby the stabilizer taxol decreased respiration (5mM ADP: control, 195.5 ± 33.6 pmol/s/mg w.w., taxol, 112.5 ± 19.6 pmols/s/mg w.w., p= 0.05) while the destabilizer vinblastine had no effect. Both stabilizer and destabilizer decreased the ability of ADP to suppress H 2 O 2 (taxol, 15 mM (p=0.03) and 100mM (p=0.02) ADP; vinblastine, 15mM to 500mM (p=0.01) ADP). No alterations were observed in succinate‐stimulated H 2 O 2 emission protocols, demonstrating that the responses in heart were surprisingly substrate‐specific. In EDL, ADP‐stimulated respiration was increased at submaximal [ADP] with destabilizer (250mM ADP: control, 15.29 ± 2.10, vinblastine, 22.75 ± 2.81 pmol/min/mg d.w., p=0.05) but did not change with stabilizer. Both drugs decreased ADP‐suppression of H 2 O 2 emission (with succinate) between 50mM to 500mM ADP (p=0.01). In soleus, ADP‐stimulated respiration and ADP‐suppression of H 2 O 2 did not change with either drug. CONCLUSIONS AND DISCUSSION Heart appears to be sensitive to microtubule‐targeted chemotherapy treatments as ADP‐stimulated respiration and suppression of H 2 O 2 were impaired. Oxidative soleus may be more resistant to alteration in microtubule structure as ADP‐stimulated respiration and suppression of H 2 O 2 did not change. In contrast, glycolytic EDL responded divergently to the destabilizer whereby ADP‐stimulated respiration was increased despite reduced ADP‐suppression of H 2 O 2 , whereas the stabilizer had no effect on respiration but also reduced ADP‐suppression of H 2 O 2. Collectively, microtubule‐stabilizing and destabilizing compounds inhibit ADP control of mitochondrial bioenergetics in heart and glycolytic skeletal muscle. Subsequent experiments will determine how these responses are related to microtubule‐VDAC binding and muscle functional capacities. Support or Funding Information Funding was provided to C.G.R.P. by National Science and Engineering Research Council (#436138‐2013) with infrastructure supported by Canada Foundation for Innovation, Ontario Research Fund and the James H. Cummings Foundation. S.V.R is supported by an OGS scholarship
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".